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Blood, 1 August 2007, Vol. 110, No. 3, pp. 962-971. Prepublished online as a Blood First Edition Paper on March 29, 2007; DOI 10.1182/blood-2007-01-066027. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-01-066027v1 110/3/962    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. Articles by Cao, X. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 3, 2007 Accepted March 27, 2007 Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4 Yuzhen Wang, Taoyong Chen, Chaofeng Han, Donghua He, Haibo Liu, Huazhang An, Zhen Cai, and Xuetao Cao* Institute of Immunology, Zhejiang University, Hangzhou, China Institute of Immunology, and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, China * Corresponding author; email: caoxt{at}public3.sta.net.cn. Toll-like receptor 4 (TLR4) can initiate both myeloid differentiation factor 88 (MyD88)-dependent and Toll/IL-1R (TIR) domain-containing adapter inducing IFN- (TRIF)-dependent signaling, leading to production of proinflammatory mediators and type I interferon to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to the pathogenesis of autoimmune and inflammatory diseases. TLR4 can be transported from plasma membrane to endosome for ubiqutination and to lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways to negative regulation of TLR4 signaling. We previously have identified a novel lysosome-associated small GTPase Rab7b that is predicted to be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate LPS-induced production of TNF-, IL-6, nitric oxide (NO) and IFN-, and potentate LPS-induced activation of mitogen-activated protein kinase (MAPK), nuclear factor B (NF- B) and interferon regulatory factor 3 (IRF-3) signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b, which is localized in LAMP-1-positive subcellular compartments and can be colocalized with TLR4 after LPS treatment, can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling potentially by promoting the translocation of TLR4 into lysosomes for degradation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: TLR4 signaling: negative regulation by degradation Osamu Takeuchi and Shizuo Akira Blood 2007 110: 794. [Full Text] [PDF] This article has been cited by other articles: T. Zhang, S. Liu, P. Yang, C. Han, J. Wang, J. Liu, Y. Han, Y. Yu, and X. Cao Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/{beta}-catenin pathway Blood, November 5, 2009; 114(19): 4081 - 4088. [Abstract] [Full Text] [PDF] M. Yao, X. Liu, D. Li, T. Chen, Z. Cai, and X. Cao Late Endosome/Lysosome-Localized Rab7b Suppresses TLR9-Initiated Proinflammatory Cytokine and Type I IFN Production in Macrophages J. Immunol., August 1, 2009; 183(3): 1751 - 1758. [Abstract] [Full Text] [PDF] C. Han, T. Chen, M. Yang, N. Li, H. Liu, and X. Cao Human SCAMP5, a Novel Secretory Carrier Membrane Protein, Facilitates Calcium-Triggered Cytokine Secretion by Interaction with SNARE Machinery J. Immunol., March 1, 2009; 182(5): 2986 - 2996. [Abstract] [Full Text] [PDF] C. Wang, T. Chen, N. Zhang, M. Yang, B. Li, X. Lu, X. Cao, and C. Ling Melittin, a Major Component of Bee Venom, Sensitizes Human Hepatocellular Carcinoma Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis by Activating CaMKII-TAK1-JNK/p38 and Inhibiting I{kappa}B{alpha} Kinase-NF{kappa}B J. Biol. Chem., February 6, 2009; 284(6): 3804 - 3813. [Abstract] [Full Text] [PDF] T. Chen, J. Guo, C. Han, M. Yang, and X. Cao Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway J. Immunol., February 1, 2009; 182(3): 1449 - 1459. [Abstract] [Full Text] [PDF] S. L. Schwartz, C. Cao, O. Pylypenko, A. Rak, and A. Wandinger-Ness Rab GTPases at a glance J. Cell Sci., November 15, 2007; 120(22): 3905 - 3910. [Full Text] [PDF]

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